Congestive heart failure (CHF) occurs in over 5 million individuals in the United States today, and 500,000 additional cases are diagnosed each year. This condition is the leading cause for inpatient hospitalizations within the U.S. and is associated with high cardaic morbidity and mortality. (A. H. Assoc. (2006) Heart and Stroke Statistical Update: American Heart Association, Dallas, Tex.) CHF, systolic or diastolic, can result from a variety of structural or functional cardiac disorders or events that impair the heart's pump function. In ischemic heart disease, one of the major causes of CHF, necrotic myocyte death produces a vicious cycle of ventricular enlargement, increased myocyte fiber stress (particularly in the border zone) and eccentric myocyte hypertrophy (post-MI remodeling). Following an acute myocardial infarction (AMI), for example, necrotic tissue is replaced by fibrotic scar tissue to maintain the integrity of the ventricle, and, around this aneurysm, the infarct or a border zone (BZ) of hypocontractile and thinned myocardium develops and becomes subjected to substantially increased myocyte fiber stresses during the cardiac cycle. These increased stresses and abnormal strain on the region has been implicated in the pathological remodeling of the ventricle after an iscehmic event, resulting in infarct extension and expansion and ultimately leading to congestive heart failure.
Attempts have also been made to address AMI injuries through various approaches. Drug therapy (ACE inhibitors and BETA blockers) has been shown to slow the remodeling that occurs after AMI, but has not been associated with return to normal left ventricular (LV) size and function. Solid organ cardiac transplantation is limited by donor shortage, and assist device therapy, although promising, is limited by persistent thrombotic events, infection, long-term materials compatibility, and the lack of an implantable power supply. Because of deficiencies in medical and standard surgical therapy for heart failure, innovative surgical procedures that reduce LV size or change LV shape are being investigated. Aneurysm repair, and radiofrequency infarct heating reduce LV volume, but LV function is either unchanged or mildly reduced. Partial left ventriculectomy reduces LV volume and wall stress, but significantly reduces LV function. Finally, passive cardiac constraint (Acorn cardiac support device, Acorn Cardiovascular) and shape change therapy with a novel tensioning device (Myosplint, Myocor) are promising, but seem unlikely to lead to large improvements in LV function.
Other approaches through tissue engineering and cell transplantation, with or without carrier matrices, into the infarct region have also been attempted to improve regional and global pump function, with mixed results. Survival of engraftment of the implanted cells has been poor and conclusive myocyte regeneration elusive despite demonstrated reduction in post-infarct loss of myocardial function with cellular and cellular/matrix injection. As such, there is a need for additional methods to stabilize the myocardium. The present invention provides compositions and methods useful in stabilizing the myocardium and mitigating function loss following ischemic injury to the heart.
Literature
                1. R. A. Stile, W. R. Burghardt, and K. E. Healy, “Synthesis and characterization of injectable poly(N-isopropylacrylamide)-based hydrogels that support tissue formation in vitro,” Macromolecules, vol. 32, pp. 7370-7379, 1999        2. S. Kim and K. E. Healy, “Synthesis and characterization of injectable poly(N-isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links,” Biomacromolecules, vol. 4, pp. 1214-1223, 2003        3. R. A. Stile and K. E. Healy, “Poly(N-isopropylacrylamide)-based semi-interpenetrating polymer networks for tissue engineering applications. 1. Effects of linear poly(acrylic acid) chains on phase behavior,” Biomacromolecules, vol. 3, pp. 591-600, 2002.        4. R. Pola, L. E. Ling, M. Silver, M. J. Corbley, M. Kearney, R. B. Pepinsky, R. Shapiro, F. R. Taylor, D. P. Baker, T. Asahara, and J. M. Isner, “The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors,” Nature Medicine, vol. 7, pp. 706-711, 2001.        5. R. J. Batista, J. Verde, P. Nery, L. Bocchino, N. Takeshita, J. N. Bhayana, J. Bergsland, S. Graham, J. P. Houck, and T. A. Salerno, “Partial left ventriculectomy to treat end-stage heart disease,” Ann Thorac Surg, vol. 64, pp. 634-8., 1997.        6. J. M Guccione, S. M. Moonly, A. W. Wallace, M. B. Ratcliffe, “Residual stress produced by ventricular volume reduction surgery has little effect on ventricular function and mechanics: A finite element model study,” Journal of Thoracic and Cardiovascular Surgery, vol. 122, pp. 592-599, 2001        7. M. B. Ratcliffe, J. Hong, A. Salahieh, S. Ruch, and A. W. Wallace, “The effect of ventricular volume reduction surgery in the dilated, poorly contractile left ventricle: a simple finite element analysis,” J Thorac Cardiovasc Surg, vol. 116, pp. 566-77., 1998.        8. H. N. Sabbah, V. G. Sharov, P. A. Chaudhry, G. Suzuki, A. Todor, and H. Morita, “Chronic therapy with the acorn cardiac support device in dogs with chronic heart failure: three and six months hemodynamic, histologic and ultrastructural findings,” J Heart Lung Transplant, vol. 20, pp. 189, 2001.        9. J. M Guccione, A Salahieh, S. M Moonly, J. Kortsmit, A. W. Wallace, M. B Ratcliffe, “Myosplint decreases wall stress depressing function in the failing heart: A finite element model study” Ann Thorac Surg, vol. 76, pp. 1171-80, 2003        10. B. M. Jackson, J. H. Gorman, S. L. Moainie, T. S. Guy, N. Narula, J. Narula, M. G. John-Sutton, L. H. Edmunds, Jr., and R. C. Gorman, “Extension of borderzone myocardium in postinfarction dilated cardiomyopathy,” J Am Coll Cardiol, vol. 40, pp. 1160-7; discussion 1168-71, 2002.        11. M. J. Moulton, S. W. Downing, L. L. Creswell, D. S. Fishman, D. M. Amsterdam, B. A. Szabo, J. L. Cox, and M. K. Pasque, “Mechanical dysfunction in the border zone of an ovine model of left ventricular aneurysm,” Ann Thorac Surg, vol. 60, pp. 986-97; discussion 998, 1995.        12. J. M. Guccione, S. M. Moonly, P. Moustakidis, K. D. Costa, M. J. Moulton, M. B. Ratcliffe, and M. K. Pasque, “Mechanism Underlying Mechanical Dysfunction in the Border Zone of Left Ventricular Aneurysm: A Finite Element Model Study,” Ann. Thorac. Surg, vol. 71 pp 654-62, 2001        13. D. Orlic, J. Kajstura, S. Chimenti, I. Jakoniuk, S. M. Anderson, B. S. Li, J. Pickel, R. McKay, B. Nadal-Ginard, D. M. Bodine, A. Leri, and P. Anversa, “Bone marrow cells regenerate infarcted myocardium,” Nature, vol. 410, pp. 701-705, 2001.        14. J. M. Guccione, K. D. Costa, A. D. McCulloch, “Finite element stress analysis of left ventricular mechanics in the beating dog heart,” J Biomechanics, vol. 28, pp. 1167-1177, 1995        15. J. H. Omens, K. D. May, A. D. McCulloch, “Transmural distribution of three-dimensional strain in the isolated arrested canine left ventricle,” Am J Physiol, vol. 261, pp. H918-28. 1991        16. J. M. Guccione, A. D. McCulloch, L. K. Waldman, “Passive material properties of intact ventricular myocardium determined from a cylindrical model” J Biomech Eng, vol. 113 pp. 42-55, 1991        17. J. M. Gucionne, L. K. Waldman, A. D McCulloch, “Mechanics of active contraction in cardiac muscle: Part II—Cylindrical models of the systolic left ventricle,” J Biomech Eng, vol. 115, pp. 82-90, 1993        18. Heart and Stroke Statistical Update: American Heart Association, Dallas; 2005.        19. Atkins B Z, Hueman M T, Meuchel J. Hutcheson K A, Glower D D, Taylor D A. Cellular cardiomyoplasty improves diastolic properties of injured heart. Journal Of Surgical Research 1999; 85(2):234-242.        20. Tomita G. Mickle D A G, Weisel R D, Jia Z C, Tumiati L C, Allidina Y. Liu P. Li R K. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. Journal of Thoracic and Cardiovascular Surgery 2002; 123(6):1132-1140.        21. Strauer B E, Brehm M. Zeus T, Kostering M. Hernandez A, Sorg R V, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106(15):1913-1918.        22. Kawamoto A, Tkebuchava T. Yamaguchi J I, Nishimura H. Yoon Y S, Milliken C. Uchida S. Masuo 0, lwaguro H. Ma H. Hanley A, Silver M, Kearney M. Losordo D. lsner J, Asahara T. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 2003; 107(3):461-468.        23. Kofidis T, Lebl D R, Martinez E C, Hoyt G, Tanaka M, Robbins R C. Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation 2005; 112(9):1173-1177.        24. Christman K L, Fok H H, Sievers R E, Fang Q H, Lee R J. Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction. Tissue Engineering 2004; 10(34):403-409.        25. Fuchs S, Baffour R, Zhou Y F, Shou M, Pierre A, Tio F O, Weissman N J, Leon M B, Epstein S E, Kornowski R. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. Journal of the American College of Cardiology 2001; 37(6):1726-1732.        26. Mangi A A, Noiseux N. Kong D L, He H M, Rezvani M, Ingwall J S, Dzau V J. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature Medicine 2003; 9(9): 1195-1201.        27. Grossman W, Jones D. McLaurin L P. Wall Stress And Patterns Of Hypertrophy In Human Left-Ventricle. Journal Of Clinical Investigation 1975; 56(1):56-64.        28. Costa K D, Hunter P J, Wayne J S, Waldman L K, Guccione J M, McCulloch A D. A three-dimensional finite element method for large elastic deformations of ventricular myocardium.2. Prolate spheroidal coordinates. Journal Of Biomechanical Engineering-Transactions Of The Asme 1996; 118(4):464-472.        29. Guccione J M, Costa K D, McCulloch A D. Finite-Element Stress-Analysis Of Left-Ventricular Mechanics In The Beating Dog Heart. Journal Of Biomechanics 1995; 28(10):1167-1177.        30. Walker J C, Ratcliffe M B, Zhang P. Wallace A W, Fata B. Hsu E W, Saloner D. Guccione J M. MRI-based finite-element analysis of left ventricular aneurysm. American Journal Of Physiology-Heart And Circulatory Physiology 2005; 289(2):H692-H700.        31. Urech L. Bittermann A G, Hubbell J A, Hall H. Mechanical properties, proteolytic degradability and biological modifications affect angiogen) c process extension into native and modified fibrin matrices in vitro. Biomaterials 2005; 26(12):1369-1379.        32. Semler E J, Ranucci C S, Moghe P V. Mechanochemical manipulation of he aggregation can selectively induce or repress liver-specific function. Biotechnology And Bioengineering 2000; 69(4):359-369.        33. Barocas V H, Moon A G, Tranquillo R T. The Fibroblast-Populated Collagen Microsphere Assay Of Cell Traction Force.2. Measurement Of The Cell Traction Parameter. Journal Of Biomechanical Engineering-Transactions Of The Asme 1995; 117(2): 161-170.        34. Stile R A, Chung E. Burghardt W R, Healy K E. Poly(N-isopropylacrylamidey based semi-interpenetrating polymer networks for tissue engineering applications. Effects of linear poly(acrylic acid) chains on rheology. Journal of Biomaterials Science-Polymer Edition 2004; 15(7):865-878.        35. Kim G. Healy K E. Synthesis and characterization of injectable poly(Nisopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links. Biomacromolecules 2003; 4(5):1214-1223.        36. Stokke B T, Draget K I, Smidsrod 0, Yuguchi Y, Urakawa H. Kajiwara K. Small-angle X-ray scattering and rheological characterization of alginate gels. 1. Ca-alginate gels. Macromolecules 2000; 33(5): 1853-1863.        37. Rizzi S C, Hubbell J A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part 1: Development and physicochernical characteristics. Biomacromolecules 2005; 6(3):1226-1238.        38. He K L, Yi G H, Sherman W, Zhou H. Zhang G P, Gu A. Kao R. Haimes H B, Harvey J. Roos E. White D. Taylor D A, Wang J. Burkhoff D. Autologous skeletal myoblast transplantation improved hemodynamics and left ventricular function in chronic heart failure dogs. Journal Of Heart And Lung Transplantation 2005; 24(11):1940-1949.        39. Wollert, K. C., Meyer, G P, Lotz, J., Ringes-Lichtenberg S, Lippolt P. Breidenbach C. Fichtner S, Korte T, Hornig B. Messinger D. Arseniev L. Hertenstein B. Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364(9429):141-148.        40. Meyer G P, Wollert K C, Lotz J. Steffens J. Lippolt P. Fichtner G. Hecker H. Schaefer A, Arseniev L. Hertenstein B. Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction—Eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006; 113(10):1287-1294.        41. van Oosterhout M F M, Arts T, Muijtjens A M M, Reneman R S, Prinzen F W. Remodeling by ventricular pacing in hypertrophying dog hearts. Cardiovascular Research 2001; 49(4):771-778.        42. Jackson B M, Gorman J H, Salgo I S, Moainie S L, Plappert T, St John-Sutton M. Edmunds L H, Gorman R C. Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. American Journal Of Physiology-Heart And Circulatory Physiology 2003; 284(2):H475-H479.        43. Moulton M J, Downing S W, Creswell L L, Fishman D S, Amsterdam D M, Szabo B A, Cox J L, Pasque M K. Mechanical Dysfunction In The Border Zone Of An Ovine Model Of Left-Ventricular Aneurysm. Annals Of Thoracic Surgery 1995; 60(4):986-998.        44. Orlic D, Kajstura J, Chimenti S, Limana F. Jakoniuk I, Quaini F. Nadal-Ginard B. Bodine D M, Led A. Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proceedings of the National Academy of Sciences of the United States of America 2001; 98(18):10344-10349.        45. Ratcliffe M B, Hong J. Salahieh A. Ruch G. Wallace A W. The effect of ventricular volume reduction surgery in the dilated, poorly contractile left ventricle: A simple finite element analysis. Journal Of Thoracic And Cardiovascular Surgery 1998; 116(4):566-577.        46. Dickstein M L, Spotnitz H M, Rose E A, Burkhoff D. Heart reduction surgery: An analysis of the impact on cardiac function. Journal Of Thoracic And Cardiovascular Surgery 1997; 113 (6):1032-1040.        